U.S. patent number 4,242,355 [Application Number 06/076,486] was granted by the patent office on 1980-12-30 for novel 3-(aminoethyl)-phenols.
This patent grant is currently assigned to Roussel Uclaf. Invention is credited to Claude Dumont, Daniel Frechet, Lucien Nedelec.
United States Patent |
4,242,355 |
Nedelec , et al. |
* December 30, 1980 |
**Please see images for:
( Certificate of Correction ) ** |
Novel 3-(aminoethyl)-phenols
Abstract
Novel derivatives of 3-(aminoethyl)-phenols of the formula
##STR1## wherein A is a simple bond or alkylene of 1 to 6 carbon
atoms and B is selected from the group consisting of aryl,
diarylmethyl, cycloalkyl of 3 to 10 carbon atoms and heteroaryl
with the proviso that B is not phenyl when A is ethylene and their
non-toxic, pharmaceutically acceptable acid addition salts having a
dopaminergic activity and their preparation.
Inventors: |
Nedelec; Lucien (Le Raincy,
FR), Frechet; Daniel (Paris, FR), Dumont;
Claude (Nogent-sur-Marne, FR) |
Assignee: |
Roussel Uclaf (Paris,
FR)
|
[*] Notice: |
The portion of the term of this patent
subsequent to December 19, 1995 has been disclaimed. |
Family
ID: |
9212922 |
Appl.
No.: |
06/076,486 |
Filed: |
September 17, 1979 |
Foreign Application Priority Data
|
|
|
|
|
Sep 22, 1978 [FR] |
|
|
78 27190 |
|
Current U.S.
Class: |
514/438; 514/400;
549/75; 564/321; 564/374; 514/415; 514/654; 564/316; 564/336 |
Current CPC
Class: |
C07D
233/64 (20130101); C07D 209/16 (20130101); A61P
25/00 (20180101); C07D 333/24 (20130101); A61P
5/00 (20180101); C07D 333/20 (20130101) |
Current International
Class: |
C07D
209/00 (20060101); C07D 233/54 (20060101); C07D
209/16 (20060101); C07D 333/20 (20060101); C07D
333/00 (20060101); C07D 233/00 (20060101); C07D
333/24 (20060101); A61K 031/38 (); A61K 031/135 ();
C07D 333/16 (); C07C 087/29 () |
Field of
Search: |
;549/75 ;424/275,330
;260/57.8R,570.9 |
References Cited
[Referenced By]
U.S. Patent Documents
Primary Examiner: Siegel; Alan
Attorney, Agent or Firm: Hammond & Littell,
Weissenberger and Muserlian
Claims
We claim:
1. A compound selected from the group consisting of
3-(aminoethyl)-phenols of the formula ##STR12## wherein A is a
simple bond or alkylene of 1 to 6 carbon atoms and B is selected
from the group consisting of phenyl, and thienyl with the proviso
that B is not phenyl when A is ethylene and their non-toxic,
pharmaceutically acceptable acid addition salts.
2. A compound of claim 1 wherein A is a simple bond or alkylene of
2 to 3 carbon atoms.
3. A compound of claim 1 wherein -A-B is selected from the group
consisting of phenylpropyl and 2-(2-thienyl)-ethyl.
4. A compound of claim 1 which is
di-[3-{2-[(3-phenylpropyl)-propylamino]-ethyl}-phenol]oxalate.
5. A compound of claim 1 which is
3-[2-propyl-2-(2-thienyl)-ethylamino]-ethyl-phenol
hydrochloride.
6. A dopaminergic composition comprising a dopaminergically
effective amount of at least one compound of claim 1 and an
excipient.
7. A composition of claim 6 wherein B is selected from the group
consisting of phenyl and thienyl.
8. A composition of claim 7 wherein A is a simple bond or alkylene
of 2 to 3 carbon atoms.
9. A composition of claim 6 wherein -A-B is selected from the group
consisting of phenylpropyl and 2-(2-thienyl)-ethyl.
10. A composition of claim 6 wherein the compound is
di-[3-}2-[(3-phenylpropyl)-propylamino]-ethyl}-phenol]oxalate.
11. A composition of claim 6 wherein the compound is
3-[2-propyl-2-(2-thienyl)-ethylamino]-ethyl-phenol
hydrochloride.
12. A method of inducing dopaminergic activity in warm-blooded
animals comprising administering to warm-blooded animals a
dopaminergically effective amount of at least one compound of claim
1.
13. A method of claim 12 wherein B is selected from the group
consisting of phenyl and thienyl.
14. A method of claim 13 wherein A is a simple bond or alkylene of
2 to 3 carbon atoms.
15. A method of claim 12 wherein -A-B is selected from the group
consisting of phenylpropyl and 2-(2-thienyl)-ethyl.
16. A method of claim 12 wherein the compound is
di-[3-}2-[(3-phenylpropyl)-propylamino]-ethyl}-phenol]oxalate.
17. A method of claim 12 wherein the compound is
3-[2-propyl-2-(2-thienyl)-ethylamino]-ethyl-phenol hydrochloride.
Description
STATE OF THE ART
U.S. Patent Application Ser. No. 905,535 filed May 12, 1978, now
U.S. Pat. No. 4,175,136, U.S. Pat. No. 4,130,658 and No. 2,525,674
and French Pat. No. 1,397,429 which corresponds to U.S. Pat. No.
3,377,359, describe compounds with related activity.
OBJECTS OF THE INVENTION
It is an object of the invention to provide the novel compounds of
formula I and their non-toxic, pharmaceutically acceptable acid
addition salts and a novel process and intermediates for their
preparation.
It is another object of the invention to provide dopaminergic
compositions and to provide a novel method of inducing dopaminergic
activity in warm-blooded animals.
These and other objects and advantages of the invention will become
obvious from the following detailed description.
THE INVENTION
The novel compounds of the invention are selected from the group
consisting of 3-(aminoethyl)-phenols of the formula ##STR2##
wherein A is a simple bond or alkylene of 1 to 6 carbon atoms and B
is selected from the group consisting of aryl, diarylmethyl,
cycloalkyl of 3 to 10 carbon atoms and heteroaryl with the proviso
that B is not phenyl when A is ethylene and their non-toxic,
pharmaceutically acceptable acid addition salts.
Examples of alkylene radicals of A are methylene, ethylene,
propylene, trimethylene, tetramethylene, pentamethylene and
hexamethylene. Example of B are aryl such as phenyl, naphthyl and
anthracenyl; diarylmethyl such as benzhydryl; cycloalkyl of 3 to 10
carbon atoms such as cyclopentyl, cyclohexyl, cycloheptyl and
adamantyl; and heteroaryl such as thienyl, indolyl, imidazolyl,
pyrrolyl and pyridyl.
Examples of suitable acids for the non-toxic, pharmaceutically
acceptable acid addition salts are inorganic acids such as
hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid,
sulfuric acid or phosphoric acid and organic acids such as acetic
acid, formic acid, benzoic acid, maleic acid, fumaric acid,
succinic acid, tartaric acid, citric acid, oxalic acid, glyoxylic
acid, asparatic acid, alkanesulfonic acids such as methane sulfonic
acid or ethane sulfonic acid, aryl sulfonic acids such as benzene
sulfonic acid or p-toluene sulfonic acid and aryl carboxylic
acids.
Among the preferred compounds of formula I are those wherein B is
phenyl, cyclopentyl, cyclohexyl, adamantyl, thienyl, indolyl or
imidazolyl and their non-toxic, pharmaceutically acceptable acid
addition salts, those wherein A is a simple bond or alkylene of 2
to 3 carbon atoms and B is phenyl, cyclopentyl, cyclohexyl,
adamantyl, thienyl, indolyl and imidazolyl and especially those
wherein A-B is phenylpropyl, cyclohexylethyl, cyclopentyl,
adamantyl, 2-(2-thienyl)-ethyl, 2-[1H-indol-3-yl]-ethyl or
2-[1H-imidazol-4-yl]-ethyl and their non-toxic, pharmaceutically
acceptable acid addition salts.
Specific preferred compounds of the invention are
di-[3-{2-[(3-phenylpropyl]-propylamino)-ethyl}-phenol]-oxalate,
3-[2-(propyl)-2-(2-thienyl)-ethyl-amino]-ethyl-phenol
hydrochloride, 3-[2-{(2-cyclohexylethyl)-propylamino}-ethyl]-phenol
hydrochloride and 3-[2-(cyclopentylpropylamino)-ethyl]-phenol
hydrochloride.
The novel process of the invention for the preparation of a
compound of formula I comprises subjecting a compound of the
formula ##STR3## wherein A and B have the above definition to
hydrolysis to obtain the corresponding compound of formula I which
may be salified, if desired.
Preferably, the hydrolysis of the compound of formula II is
effected with concentrated hydrobromic acid or pyridine
hydrochloride at reflux. The hydrolysis is advantageously followed
by alkalinization with ammonium hydroxide to obtain the free base
of formula I. To form the acid addition salts, approximately
equimolar amounts of the compound of formula I and the acid are
reacted.
The novel dopaminergic compositions are comprised of a
dopaminergically effective amount of at least one compound of
formula I and their non-toxic, pharmaceutically acceptable acid
addition salts and an inert pharmaceutical carrier or excipient.
The composition may be in the form of tablets, coated tablets
gelules, capsules, granules, suppositories and injectable solutions
or suspensions.
Examples of suitable excipients or pharmaceutical carriers are
talc, arabic gum, lactose, starch, magnesium stearate, cacao
butter, aqueous and non-aqueous vehicles, fatty bodies of animal or
vegetable origin, paraffinic derivatives, glycols, preservatives,
diverse wetting agents, emulsifiers or dispersants.
The compositions of the invention possess remarkable susceptible
dopaminergic properties making them useful for treating
neurological syndromes of extrapyramidal origin and inhibiting the
secretion of prolactin. They are useful for treatment of the
symptoms of Parkinson disease, treatment of post-encephalitic
parkinson syndromes and of arteriosclerous origin or toxic etiology
as well as treating troubles of hyperprolactinemia.
Among the preferred compositions of the invention are those wherein
B is phenyl, cyclopentyl, cyclohexyl, adamantyl, thienyl, indolyl
or imidazolyl and their non-toxic, pharmaceutically acceptable acid
addition salts, those wherein A is a simple bond or alkylene of 2
to 3 carbon atoms and B is phenyl, cyclopentyl, cyclohexyl,
adamantyl, thienyl, indolyl and imidazolyl and especially those
wherein A-B is phenylpropyl, cyclohexylethyl, cyclopentyl,
adamantyl, 2-(2-thienyl)-ethyl, 2-[1H-indol-3-yl]-ethyl or
2-[1H-imidazol-4-yl]-ethyl and their non-toxic, pharmaceutically
acceptable acid addition salts.
Specific preferred compositions of the invention are
di-[3-{2-[(3-phenylpropyl]-propylamino)-ethyl}-phenol]-oxalate,
3-[2-(propyl)-2-(2-thienyl)-ethylamino]-ethyl-phenol hydrochloride,
3-[2{-(2-cyclohexylethyl)-propylamino}-ethyl]-phenol hydrochloride
and 3-[2-(cyclopentylpropylamino)-ethyl]-phenol hydrochloride.
The novel method of the invention for treating the syndromes of
Parkinson disease in warm-blooded animals including humans
comprises administering to warm-blooded animals a dopaminergically
effective amount of at least one compound of formula I and its
non-toxic, pharmaceutically acceptable acid addition salts. The
compounds may be administered orally, rectally or parenterally and
the usual daily dose is 0.2 to 10 mg/kg by oral route in man.
The compounds of formula II wherein A is alkylene of 1 to 3 carbon
atoms and B has the above definition may be prepared by reacting a
compound of the formula ##STR4## with a halide of the formula
wherein A and B have the above definition and Hal is a chlorine
bromine, or iodine atom. The reaction is preferably effected in an
alkanol such as ethanol in the presence of an alkaline agent such
as sodium carbonate or potassium carbonate or in the presence of an
organic base such as triethylamine at reflux.
The compounds of formula II wherein A is alkylene of 2 to 6 carbon
atoms may be prepared by reacting the compound of formula III with
an acid of the formula
wherein B has the above definition and A' is alkylene of 1 to 5
carbon atoms to form a compound of the formula ##STR5## and
reducing the latter to the corresponding compound of formula
II.
The reaction of the compounds of formula III and V is preferably
effected at reflux in the presence of dicyclohexylcarbodiimide. The
reduction of the compound of formula VI is preferably effected with
lithium aluminum hydride or diborane or a complex of diborane and
dimethylsulfide in an organic solvent such as tetrahydrofuran.
The compounds of formula II wherein A is alkylene of 2 to 6 carbon
atoms may also be prepared by reacting a compound of the formula
##STR6## with an acid of formula V to obtain a compound of the
formula ##STR7## reducing the latter to obtain a compound of the
formula ##STR8## and reacting the latter with a propyl halide such
as the chloride, bromide or iodide to obtain the corresponding
compound of formula II.
The condensation with the acid of formula V and the reduction step
may be effected as described previously. The reaction of the
compound of formula IX with the propyl halide is preferably
effected in an organic solvent such as acetone or methyl ethyl
ketone in the presence of an alkaline agent such as potassium
carbonate at reflux temperatures.
The products of formula II may also be prepared by reacting the
acid of the formula ##STR9## with an amine of the formula
wherein B and A have the above definitions to obtain a compound of
the formula ##STR10## reducing the latter to form a compound of
formula IX and reacting the latter as above. The reduction is
preferably effected with lithium aluminum hydride.
The compounds of formula III may be prepared by reacting the
compound of formula VII with a propyl halide or by reacting a
compound of formula VII with propionic acid to obtain a compound of
the formula ##STR11## and reducing the latter.
The novel intermediates of the invention are those of formula
II.
In the following examples there are described several preferred
embodiments to illustrate the invention. However, it should be
understood that the invention is not intended to be limited to the
specific embodiments.
EXAMPLE 1
di-[3-{2-[(3-phenylpropyl)-propylamino]-ethyl}-phenol]oxalate
STEP A: 3-methoxy-N-propyl-benzeneethanamine
A mixture of 10 g of 3-methoxy-benzeneethanamine, 11.25 g of
1-iodopropane and 66 ml of triethylamine was refluxed with stirring
under an inert atmosphere for 90 minutes and was then distilled to
dryness under reduced pressure. 250 ml of 0.5 N ammonium hydroxide
solution were added to the residue and the mixture was extracted
with ethyl acetate. The organic phase was washed with water, dried
and evaporated to dryness under reduced pressure to obtain 12.1 g
of an oil. The latter was chromatographed over silica gel and was
eluted with a 7-3 chloroform-methanol mixture to obtain 8 g of
product. The latter was dissolved in 20 ml of ethyl acetate and an
ethyl acetate solution saturated with hydrogen chloride was added
thereto dropwise until a pH of 1 was reached. Crystallization
occurred and the mixture was vacuum filtered to obtain 7.2 g of
3-methoxy-N-propyl-benzeneethanamine hydrochloride melting at
182.degree. C.
STEP B:
N-[2-(3-methoxyphenyl)-ethyl]-N-propylbenzene-propanamine
A stirred suspension of 6 g of the product of Step A, 12 g of
3-phenylpropyl bromide, 12 g of potassium carbonate and 100 ml of
acetone under nitrogen was refluxed for 40 hours and was then
cooled to room temperature and poured into 500 ml of water. The
mixture was extracted with methylene chloride and the organic phase
was dried and evaporated to dryness under reduced pressure to
obtain 12 g of a yellow oil. The latter was taken up in 1 N
hydrochloric acid and the mixture was washed with ether and made
alkaline by addition of sodium hydroxide at about 10.degree. C. The
resulting precipitate was extracted with methylene chloride and the
organic phase was dried and evaporated to dryness under reduced
pressure to obtain 9.5 g of
N-[2-(3-methoxyphenyl)-ethyl]-N-propylbenzenepropanamine in the
form of a yellow oil which was used as is for the next step.
STEP C: di-[3-{2-[(3-phenylpropyl)-propylamino]-ethyl}-phenol]
oxalate
A stirred mixture of 9.5 g of the product of Step B in 50 ml of 48%
hydrobromic acid was refluxed under an inert atmosphere for 90
minutes and the mixture was cooled to 20.degree. C. and was make
alkaline with concentrated ammonium hydroxide. The mixture was
extracted with methylene chloride and the organic phase was dried
and evaporated to dryness under reduced pressure to obtain 9 g of a
yellow oil residue. The residue was dissolved in 10 ml of methanol
and 1.9 g of oxalic acid dihydrate were added thereto. The mixture
was heated to 40.degree. C. until dissolution occured and 50 ml of
ethyl acetate were added thereto. The mixture was concentrated to a
volume of 50 ml and was vacuum filtered to obtain 6.5 g of
di-[3-{2-[(3-phenylpropyl)-propylamino]-ethyl}-phenol] oxalate
melting at 145.degree. C. The product was dissolved in 60 ml of
methanol and the solution was filtered. 100 ml of ethyl acetate
were added to the filtrate and the mixture was concentrated to 60
ml and was vacuum filtered to obtain 5.5 g of the product melting
at 145.degree. C.
Analysis: (C.sub.20 H.sub.27 NO).sub.2.(COOH).sub.2 ; molecular
weight=684.88: Calculated: %C 73.65; %H 8.24; %N 4.09; Found: %C
73.5; %H 8.4; %N 3.8
UV Spectrum (ethanol):
Inflex.--215 nm E.sub.1.sup.1 =367
Inflex.--223 nm E.sub.1.sup.1 =184
Inflex.--268 nm E.sub.1.sup.1 =51
Max.--273 nm E.sub.1.sup.1 =61 .epsilon.=2100
Inflex.--279 nm E.sub.1.sup.1 =55
U.V. Spectrum (ethanol - N/10 NaOH):
Max.--240 nm E.sub.1.sup.1 =289 .epsilon.=9900
Inflex.--269 nm E.sub.1.sup.1 =38
Max.--290-291 nm E.sub.1.sup.1 =98 .epsilon.=3350
EXAMPLE 2
3-[2-propyl-2-(2-thienyl)-ethylamino]-ethyl-phenol
hydrochloride
STEP A: N-[2-(3-methoxyphenyl)-ethyl]-2-thiophene-acetamide
A mixture of 15.1 g of 3-methoxy-benzeneethanamine and 14.2 g of
.alpha.-thienylacetic acid was stirred at 200.degree. C. under an
inert atmosphere for 30 minutes and was then cooled to 20.degree.
C. 600 ml of a refluxing 1-1 ether-isopropyl ether mixture were
added thereto and the mixture was filtered. The filtrate was
evaporated to dryness under reduced pressure to obtain 28 g of a
brown oil. The oil was crystallized from 28 ml of ether at
5.degree. C. and the mixture was vacuum filtered to obtain 25.5 g
of N-[2-(3-methoxyphenyl)-ethyl]-2-thiopheneacet amide melting at
50.degree. C.
STEP B: N-[2-(3-methoxyphenyl)-ethyl]-2-thiophenethanamine
hydrochloride
21.9 ml of a complex of borane-dimethylsulfide were added all at
once at room temperature to a solution of 21.90 g of the product of
Step A in 219 ml of anhydrous tetrahydrofuran and the mixture was
progressively heated to reflux and held at reflux for one hour. The
mixture was cooled to 5.degree. C. and 100 ml of 2 N hydrochloric
acid were cautiously added thereto. The mixture was refluxed for
one hour and the tetrahydrofuran was then distilled under reduced
pressure. 300 ml of water were added thereto and the mixture was
washed with ether. The organic phase was made alkaline with
concentrated ammonium hydroxide and was extracted with methylene
chloride. The organic phase was dried and evaporated to dryness
under reduced pressure to obtain 21.5 g of yellow oil residue. The
oil was dissolved in 50 ml of water and a solution of hydrogen
chloride in ethyl acetate was added to the solution until the pH
was 2. The mixture was vacuum filtered and the recovered product
was washed with ether to obtain 21.70 g of
N-[2-(3-methoxyphenyl)-ethyl]-2-thiophenethanamine hydrochloride
melting at 170.degree. C.
Analysis: C.sub.15 H.sub.19 NOS.HCl; molecular weight=297.84:
Calculated: %C 60.48; %H 6.77; %N 4.70; %Cl 11.95; %C 10.76; Found:
%C 60.6; %H 6.8; %N 4.5; %Cl 12.0; %C 10.6
UV Spectrum (ethanol):
Max.--224 nm E.sub.1.sup.1 =435 .epsilon.=13,000
Inflex.--234 nm E.sub.1.sup.1 =283
Max.--274 nm E.sub.1.sup.1 =65 .epsilon.=1,950
Max.--280-281 nm E.sub.1.sup.1 =60 .epsilon.=1,800
IR Spectrum (CHCl.sub.3): Absorption in general region-aromatic at
1605, 1589, 1490 cm.sup.-1
STEP C:
N-[2-(3-methoxyphenyl)-ethyl]-N-propyl-2-thiopheneethanamine
A stirred mixture of 21.70 g of the product of Step B, 50 g of
1-iodopropane, 50 g of potassium carbonate and 400 ml of absolute
ethanol was refluxed for 61/2 hours and the ethanol was distilled
under reduced pressure. 500 ml of water and 50 ml of sodium
hydroxide solution were added thereto and the mixture was extracted
with methylene chloride. The organic phase was washed with aqueous
sodium chloride solution, dried and evaporated to dryness under
reduced pressure to obtain 22 g of
N-[2-(3-methoxyphenyl)-ethyl]-N-propyl-2-thiopheneethanamine which
was used as is for the next step.
STEP D: 3-[2-propyl-2-(2-thienyl)-ethylamino]-ethyl-phenol
hydrochloride
A stirred mixture of 21 g of the product of Step C, 42 ml of acetic
acid and 42 ml of 48% hydrobromic acid was refluxed under an inert
atmosphere for 5 hours and was then cooled. 500 ml of ice and then
100 ml of concentrated ammonium hydroxide were added to the mixture
and the resulting mixture was extracted with methylene chloride.
The organic phase was washed with aqueous sodium chloride solution,
dried and evaporated to dryness under reduced pressure to obtain 21
g of oil residue. The oil was dissolved in 21 ml of isopropanol and
a solution of hydrogen chloride in ethyl acetate was added thereto
at 5.degree. C. until the pH was 1. Crystallization was effected
and the mixture was vacuum filtered. The recovered product was
washed with isopropanol and then with ether to obtain 16.5 g of
3-[2-propyl-2-(2-thienyl)-ethylamino]-ethyl-phenol hydrochloride
melting at .about.140.degree. C.
The said product was dissolved in 20 ml of methanol and 1.5 liters
of methylene chloride at reflux and the solution was treated with
activated carbon and was filtered. The filtrate was reduced to a
volume of 50 ml and was then added to 300 ml of ethyl acetate. The
mixture stood at room temperature for 2 hours and was then vacuum
filtered. The recovered product was washed with ethyl acetate and
dried at 90.degree. C. under reduced pressure to obtain 14 g of
product. The latter was dissolved in 400 ml of refluxing
isopropanol and the mixture was filtered and reduced to a volume of
75 ml. After crystallization, the mixture was vacuum filtered and
the 13 g of recovered product was taken up in 150 ml of refluxing
ethanol. The mixture was filtered and the filtrate was reduced to a
volume of 50 ml. After crystallization, the mixture was vacuum
filtered and the recovered product was washed with ethanol, then
ether and dried at 85.degree. C. under reduced pressure to obtain
11.8 g of the said hydrochloride melting at 145.degree. C.
Analysis: C.sub.17 H.sub.23 NOS. HCl; molecular weight=325.89:
Calculated: %C 62.65; %H 7.42; %N 4.30; %Cl 10.88; %S 9.84; Found:
%C 62.5; %H 7.6; %N 4.1; %Cl 11.0; %S 9.7
UV Spectrum (ethanol):
Max.--225 nm E.sub.1.sup.1 =360 .epsilon.=11,700
Inflex.--235 nm E.sub.1.sup.1 =258
Max.--247 nm E.sub.1.sup.1 =66 .epsilon.=2,150
Inflex.--278 nm E.sub.1.sup.1 =61
IR Spectrum (Nujol): associated OH at 3180 cm.sup.-1 ; aromatic at
1615, 1590 and 1486 cm.sup.-1.
UV Spectrum (ethanol--0.1 NaOH):
Max.--237 nm E.sub.1.sup.1 =514 .epsilon.=16,800
Max.--290-291 nm E.sub.1.sup.1 =98 .epsilon.=3,200
EXAMPLE 3
3-[2-{(2-cyclohexylethyl)-propylamino}-ethyl]-phenol
hydrochloride
STEP A: N-[2-(3-methoxyphenyl)-ethyl]-cyclohexane-acetamide
A stirred mixture of 20 g of 3-methoxy-benzeneethanamine and 15.2 g
of cyclohexylacetic acid was heated at 190.degree.-200.degree. C.
under an inert atmosphere for 45 minutes and was then cooled to
30.degree. C. The product was dissolved in ethyl acetate and the
solution was washed successively with N sodium hydroxide solution,
N hydrochloric acid and water and was evaporated to dryness. The 29
g of oil residue was crystallized from petroleum ether
(b.p.=40.degree.-70.degree. C.) and the product was dried to obtain
21.3 g of N-[2-(3-methoxyphenyl)-ethyl]cyclohexane-acetamide in the
form of a white solid melting at 74.degree. C.
STEP B: N-(2-cyclohexylethyl)-3-methoxy-benzeneethanamine
hydrochloride
A solution of 21.3 g of the product of Step A in 100 ml of
tetrahydrofuran was added over 20 minutes at 0.degree. C. to a
suspension of 11.8 g of lithium aluminum hydride in 150 ml of
tetrahydrofuran and the mixture was heated to reflux for 4 hours.
After the addition of 6 g of lithium aluminum hydride thereto, the
mixture was refluxed for another 6 hours. After 22 hours, 500 ml of
tetrahydrofuran containing 20% water were added thereto at
20.degree.-30.degree. C. and the mixture was filtered. The filtrate
was distilled and was then extracted with methylene chloride. The
organic phase was washed with water, dried and evaporated to
dryness. The 19.4 g of oil residue were dissolved in 100 ml of
ethyl acetate and an excess of ethyl acetate containing hydrogen
chloride was added thereto. The mixture was held in a refrigerator
for one hour and was then vacuum filtered. The recovered product
was washed with ethyl acetate and dried to obtain 20.6 g of
N-(2-cyclohexylethyl)-3-methoxy-benzeneethanamine hydrochloride
melting at 174.degree. C.
STEP C:
N-(2-cyclohexylethyl)-3-methoxy-N-propyl-benzeneethanamine
48 g of potassium carbonate were added to a solution of 17.8 g of
the product of Step B in 180 ml of acetone and after the addition
of 17.5 ml of 1-iodopropane, the mixture was refluxed under an
inert atmosphere for 41/2 hours and was filtered. The filtrate was
evaporated to dryness and the residue was taken up in ether. 100 ml
of 2 N sodium hydroxide solution was added to the mixture and the
decanted organic phase was washed with water, dried and evaporated
to dryness to obtain 19.25 g of
N-(2-cyclohexylethyl)-3-methoxy-N-propyl-benzeneethanamine in the
form of a yellow oil which was used as is for the next step.
STEP D:
3-[2-{(2-cyclohexylethyl)-propylamino}-ethyl]-phenolhydrochloride
A stirred mixture of 19.25 g of the product of Step C in 95 ml of
48% hydrobromic acid was refluxed under an inert atmosphere for 90
minutes and was then cooled and made alkaline by addition of
concentrated ammonium hydroxide. The mixture was saturated with
sodium chloride and was extracted with ethyl acetate. The organic
phase was washed with water, dried and evaporated to dryness. The
19 g of oil residue were dissolved in 50 ml of methyl ethyl ketone
and an excess of ethyl acetate containing hydrogen chloride was
added thereto. Crystallization was induced and the mixture was
stored in a refrigerator overnight and was vacuum filtered. The
recovered product was dried at 60.degree. C. under reduced pressure
to obtain 17.4 g of product which was crystallized twice from
methyl ethyl ketone to obtain 16.35 g of
3-[2-{(2-cyclohexylethyl)propylamine}-ethyl]-phenol hydrochloride
melting at 100.degree. C.
Analysis: C.sub.19 H.sub.31 NO.HCl; molecular weight=325.92:
Calculated: %C 70.02; %H 9.90; %N 4.30; %Cl 10.88; Found: %C 70.0;
%H 9.9; %N 4.2; %Cl 10.8
UV Spectrum (ethanol):
Max.--217 nm E.sub.1.sup.1 =184 .epsilon.=6,000
Max.--275 nm E.sub.1.sup.1 =64 .epsilon.=2,100
Inflex.--279 nm E.sub.1.sup.1 =59
UV Spectrum (ethanol--0.1 N NaOH):
Max.--239 nm E.sub.1.sup.1 =285 .epsilon.=9,300
Max.--291 nm E.sub.1.sup.1 =98 .epsilon.=3,200
EXAMPLE 4
3-[2-(propyl-{tricyclo-(3,3,1,1.sup.3-7)-decan-1-yl}-amino)-ethyl]-phenol
hydrochloride
STEP A:
3-methoxy-N-[tricyclo-(3,3,1,1.sup.3-7)-decan-1-yl]-benzeneacetamide
A mixture of 33.4 g of 3-methoxy-benzene acetic acid, 15 g of
1-amino-adamantane, 40 g of dicyclohexylcarbodiimide and 500 ml of
ethyl acetate was stirred at room temperature under an inert
atmosphere for one hour and was then filtered. The filter was
washed with ethyl acetate and the filtrate was washed 3 times with
200 ml of N sodium hydroxide solution, twice with 200 ml of N
hydrochloric acid and once with 200 ml of water. The filtrate was
then dried and evaporated to dryness under reduced pressure to
obtain 40 g of a yellow oil which was crystallized from 30 ml of
isopropyl ether to obtain 22.2 g of crystalline
3-methoxy-N-[tricyclo-(3,3,1,1.sup.3-7)-decan-1-yl]-benzene-acetamide
melting at 116.degree. C.
STEP B:
3-methoxy-N-[tricyclo-(3,3,1,1.sup.3-7)-decan-1-yl]benzeneethanamine
hydro chloride
22.2 g of the product of Step A were added over 5 minutes at
5.degree. C. to a suspension of 9 g of lithium aluminum hydride
hydride in 200 ml of tetrahydrofuran and the mixture was refluxed
with stirring for 100 minutes and was then cooled to 10.degree. C.
40 ml of tetrahydrofuran containing 50% of water were added
dropwise to the mixture over 20 minutes and the mixture was
filtered. The filtrate was evaporated to dryness and the 20 g of
colorless oil residue were dissolved in 20 ml of ethyl acetate. A
solution of ethyl acetate saturated with hydrogen chloride was
added to the solution dropwise until the pH was 1 and the mixture
was vacuum filtered to obtain 15 g of
3-methoxy-N-[tricyclo-(3,3,1,1.sup.3-7)-decan-1-yl]-benzeneethanamine
hydrochloride in the form of crystals melting at 226.degree. C.
STEP C:
3-methoxy-N-propyl-N-[tricyclo-(3,3,1,1.sup.3-7)-decan-1-yl]-benzeneethana
mine hydrochloride
A mixture of 8.7 g of the product of Step B, 10 g of
1-iodo-propane, 10 g of potassium carbonate was refluxed under an
inert atmosphere for 21/2 hours and was then cooled. The mixture
was extracted 3 times with 100 ml of methylene chloride and the
organic phase was washed twice with 100 ml of water, dried over
magnesium sulfate and filtered. The filtrate was evaporated to
dryness under reduced pressure to obtain 11.2 g of a yellow oil.
The oil was chromatographed over silica gel and was crystallized to
obtain 5.2 g of
3-methoxy-N-propyl-N-[tricyclo-(3,3,1,1.sup.3-7)decan-1-yl]-benzeneethanam
ine hydrochloride melting at 174.degree. C.
STEP D:
3-[2-(propyl-{tricyclo-(3,3,1,1.sup.3-7)-decan-1-yl}amino)-ethyl]-phenol
hydrochloride
A stirred mixture of 10.4 g of the product of Step C and 104 ml of
48% hydrobromic acid was refluxed under an inert atmosphere for one
hour and was then cooled and made alkaline with concentrated
ammonium hydroxide. The mixture was extracted 3 times with 80 ml of
methylene chloride and the organic phase was washed with 100 ml of
water, dried over magnesium sulfate and filtered. The filtrate was
evaporated to dryness and the 8.2 g of yellow oil residue was
dissolved in 20 ml of ethyl acetate. A solution of ethyl acetate
saturated with hydrogen chloride was added dropwise to the mixture
until the pH was 1 and the mixture was vacuum filtered. The
recovered product was successively crystallized from methanol and
isopropanol and then methanol and ethyl acetate. The mixture was
vacuum filtered to obtain 5.9 g of
3-[2-(propyl-{tricyclo-(3,3,1,1.sup.3-7)-decan-1-yl}-amino)-ethyl]phenol
hydrochloride melting at 220.degree. C.
Analysis: C.sub.21 H.sub.31 NO.HCl; molecular weight=349.935:
Calculated: %C 72.07; %H 9.22; %N 4.00; %Cl 10.13; Found: %C 72.2;
%H 9.4; %N 3.9; %Cl 10.2
UV Spectrum (ethanol):
Max.--217 nm E.sub.1.sup.1 =185 .epsilon.=6,500
Max.--275 nm E.sub.1.sup.1 =62 .epsilon.=2,150
Inflex.--279 nm E.sub.1.sup.1 =56
UV Spectrum (ethanol--0.1 NaOH):
Max--240 nm E.sub.1.sup.1 =267 .epsilon.=9,300
Max.--292 nm E.sub.1.sup.1 =90 .epsilon.=3,150
EXAMPLE 5
3-[2-(cyclopentylpropylamino)-ethyl]-phenol hydrochloride
STEP A: N-cyclopentyl-3-methoxy-N-propyl-benzeneethanamine
A stirred mixture of 3.4 g of 3-methoxy-N-propyl-benzeneethanamine,
4 g of potassium carbonate and 15 ml of cyclopentyl bromide was
refluxed for one hour after which 5 g of potassium carbonate were
added thereto and the mixture was refluxed for another 3 hours. The
mixture was poured into 50 ml of water and the mixture was
extracted 3 times with 50 ml of ether. The organic phase was dried
and filtered and the filtrate was evaporated to dryness to obtain
4.5 g of N-cyclopentyl-3-methoxy-N-propylbenzeneethanamine in the
form of a red oil which was used as is for the next step.
STEP B: 3-[2-(cyclopentylpropylamino)-ethyl]-phenol
hydrochloride
A stirred mixture of 4.35 g of the product of Step A and 43 ml of
48% hydrobromic acid was refluxed under a nitrogen atmosphere for 2
hours and the mixture was cooled and made alkaline by addition of
concentrated ammonium hydroxide. The mixture was extracted 3 times
with methylene chloride and the combined organic phases were washed
twice with 50 ml of water, dried over magnesium sulfate and
filtered. The filtrate was evaporated to dryness and the 4 g of
brown oil residue were dissolved in 5 ml of methanol. A solution of
ethyl acetate saturated with hydrogen chloride was added to the
mixture dropwise until the pH was acidic and the mixture was vacuum
filtered. The recovered product was crystallized from methanol and
ethyl acetate to obtain 2.7 g of
3-[2-(cyclopentylpropylamino)-ethyl]-phenol hydrochloride melting
at 140.degree. C.
Analysis: C.sub.16 H.sub.25 NO.HCl; molecular weight=283.84
Calculated: %C 67.7; %H 9.23; %N 4.94; %Cl 12.49; Found: %C 67.5;
%H 9.5; %N 4.7; %Cl 12.7
UV Spectrum (ethanol):
Max.--218 nm E.sub.1.sup.1 =229 .epsilon.=6,500
Max.--274 nm E.sub.1.sup.1 =76 .epsilon.=2,200
Inflex.--279 nm E.sub.1.sup.1 =69
UV Spectrum (ethanol--0.1 N NaOH):
Max.--241-242 nm E.sub.1.sup.1 =329 .epsilon.=9,300
Max.--291 nm E.sub.1.sup.1 =113 .epsilon.=3,200
EXAMPLE 6
3-[2-(2-{1H-imidazol-4-yl}-ethyl)-propylamino-ethyl]-phenol
oxalate
STEP A:
3-methoxy-N-[2-(1H-imidazol-4-yl)-ethyl]-benzeneethanamine
A solution of 27.6 g of histamine dihydrochloride in 150 ml of 2 N
sodium hydroxide was evaporated to dryness and the residue and 24.9
g of 3-methoxy-benzene acetic acid were stirred at 210.degree. C.
for 30 minutes and was then cooled to 50.degree. C. One liter of
refluxing ethyl acetate was added thereto and the mixture was
filtered. The filtrate ws evaporated to dryness under reduced
pressure and the residue was crystallized from methylene chloride
to obtain 27.7 g of
3-methoxy-N-[2-(1H-imidazol-4-yl)-ethyl]-benzeneethanamine melting
at 98.degree. to 100.degree. C.
STEP B: N-[2-(3-methoxyphenyl)-ethyl]-1-H-imidazol-4-ethanamine
dihydrochloride
A stirred mixture of 5 g of the product of Step A, 2.5 g of lithium
aluminum hydride and 50 ml of tetrahydrofuran was refluxed for 90
minutes and was then cooled to 10.degree. C. 100 ml of
tetrahydrofuran containing 20% water and 100 ml of methylene
chloride were added thereto and the mixture was filtered. The
filtrate was evaported to dryness and the 4.7 g of yellow oil
residue were dissolved in 30 ml of isopropanol. A solution of ethyl
acetate saturated with hydrogen chloride was added thereto to
adjust the pH to 1 and the mixture was vacuum filtered. The
recovered product was washed with isopropanol to obtain 3 g of
N-[2-(3-methoxyphenyl)-ethyl]-1H-imidazol-4-ethanamine
dihydroch1oride in the form of brilliant colorless platelets
melting at 195.degree.-198.degree. C.
STEP C:
N-[2-(3-methoxyphenyl)-ethyl]-N-propyl-1H-imidazol-4-ethanamine
A stirred mixture of 3.2 g of the product of Step B, 5.1 g of
potassium carbonate, 3.4 g of 1-iodopropane and 64 ml of acetone
was refluxed under an inert atmosphere for 19 hours and the acetone
was evaporated. 100 ml of water and 2 ml of sodium hydroxide were
added to the mixture which was then extracted 3 times with 50 ml of
methylene chloride. The combined organic phases were washed with
100 ml of water, dried over magnesium sulfate and filtered. The
filtrate was evaporated to dryness and the 3.6 g of oil residue
were chromatographed over silica gel to obtain 900 mg of
N-[2-(3-methoxyphenyl)-ethyl]-N-propyl-1H-imidazol-4-ethanamine in
the form of a yellow oil which was used as is for the next step.
C.C.M. over silica (7-3 CHCl.sub.3 -Methanol): Rf=0.20.
STEP D: 3-[2-(2-{1H-imidazol-4-yl}-ethyl)propylaminoethyl]phenol
oxalate
A stirred mixture of 800 mg of the product of Step C, 4 ml of
acetic acid and 4 ml of 48% hydrobromic acid was refluxed under an
inert atmosphere for 90 minutes and was then cooled and mixed with
ice. The mixture was made alkaline by addition of concentrated
ammonium hydroxide and was extracted 3 times with 20 ml of
methylene chloride. The organic phase was dried over magnesium
sulfate and was filtered and the filtrate was evaporated to
dryness. The 800 mg of yellow oil residue were dissolved in 5 ml of
methanol and 365 mg of oxalic acid dihydrate were added thereto.
The mixture was heated until dissolution occured and was cooled and
vacuum filtered to obtain 600 mg of product melting at 165.degree.
C., then 170.degree. C. The product was crystallized twice from
methanol to obtain
3-[2-(2-{1H-imidazol-4-yl}-ethyl)-propylaminoethyl]-phenol oxalate
melting at 170.degree. C.
Analysis: C.sub.18 H.sub.25 N.sub.3 O.sub.5 : molecular
weight=363.40: Calculated: %C 59.49; %H 6.93; %N 11.56; Found: %C
59.0; %H 6.8; %N 11.4
UV Spectrum (ethanol):
Inflex.--214 nm E.sub.1.sup.1 =336 .epsilon.=12,200
Max.--274 nm E.sub.1.sup.1 =56 .epsilon.=2,050
Inflex.--280 nm E.sub.1.sup.1 =51
UV Spectrum (ethanol--0.1 N NaOH):
Max.--240 nm E.sub.1.sup.1 =267 .epsilon.=9,700
Max.--291 nm E.sub.1.sup.1 =45 .epsilon.=3,450
EXAMPLE 7
3-[2-({2-(1H-indol-3-yl)-ethyl}-propylamino)-ethyl]-phenol
hydrochloride
STEP A: 3-methoxy-N-[2-(1H-indol-3-yl)-ethyl]-benzeneacetamide
A mixture of 29 g of tryptamine and 30 g of 3-methoxy-phenylacetic
acid was heated at 200.degree. C. for one hour and after cooling
the mixture to 50.degree. C., the mixture was dissolved in 200 ml
of ethyl acetate. The organic phase was washed successively with N
hydrochloric acid, with water, with 2 N sodium hydroxide and with
water and was dried and evaporated to dryness. The 59 g of red oil
were crystallized from ether and the mixture was vacuum filtered.
The product was dried to obtain 47.2 g of
3-methoxy-N-[2-(1H-indol-3-yl)-ethyl]-benzeneacetamide in the form
of a beige solid melting at 78.degree. C. which was used as is for
the next step. A sample recrystallized from ether melted at
82.degree. C.
STEP B: N-[2-(3-methoxyphenyl)-ethyl]-1H-indol-3-ethanamine
hydrochloride
21 ml of a complex of borane-dimethylsulfide (titrating at 1
ml.apprxeq.1 mmole) were slowly added under an inert atmosphere to
a solution of 30.6 g of the compound of Step A in 150 ml of
tetrahydrofuran and the mixture was refluxed for 135 minutes and
was cooled to 20.degree.-25.degree. C. 150 ml of 2 N hydrochloric
acid were slowly added thereto and the mixture was refluxed for 2
hours. Then, the tetrahydrofuran was evaporated and 50 ml of sodium
hydroxide solution were added to make the mixture alkaline. The
mixture was extracted with ethyl acetate and the organic phase was
washed with water, dried over magnesium sulfate and evaporated to
dryness. The 32 g of orange oil residue was chromatographed over
silica gel and were eluted with an 80-15-5 methylene
chloride-methanol-acetic acid mixture to obtain 22 g of an acetate
with an Rf=0.37. The product was neutralized with 6 N sodium
hydroxide solution and the mixture was extracted with ethyl
acetate. The organic phase was washed with water, dried and
evaporated to dryness. The 14 g of orange oil residue were
dissolved in 70 ml of ethyl acetate and an excess of ethyl acetate
saturated with hydrogen chloride was added thereto. The mixture was
vacuum filtered and the recovered product was washed with ethyl
acetate and dried to obtain 13.95 g of
N-[2-(3-methoxyphenyl)-ethyl]-1H-indol-3-ethanamine hydrochloride
in the form of a beige product melting at 164.degree. C., then
177.degree. C. which was used as is for the next step.
STEP C:
N-[2-(3-methoxyphenyl)-ethyl]-N-propyl-1H-indol-3-ethanamine
hydrochloride
The product of Step B was empasted with 100 ml of water and then an
excess of ammonium hydroxide was added thereto. The mixture was
extracted with ethyl acetate and to dryness. The 13 g of orange oil
residue were dissolved in 200 ml of acetone and 29.3 g of potassium
carbonate and 9.6 ml of 1-iodopropane were added thereto. The
mixture was refluxed for 6 hours and was filtered and the filtrate
was evaporated to dryness. The residue was taken up in 100 ml of 2
N sodium hydroxide solution and the mixture was extracted with
ethyl acetate. The organic phase was washed with water, dried and
evaporated to dryness. The 15 g of orange oil residue were
dissolved in 80 ml of ethyl acetate and an excess of ethyl acetate
saturated with hydrogen chloride was added thereto. After
crystallization, the mixture was concentrated and placed in a
refrigerator overnight. The mixture was vacuum filtered and the
recovered product was washed with ethyl acetate and dried to obtain
12.6 g of
N-[2-(3-methoxyphenyl)-ethyl]-N-propyl-1H-indol-3-ethanamine
hydrochloride melting at 140.degree. C.
STEP D: 3-[2-{2-(1H-indol-3-yl)-ethyl}-propylamino)-ethyl]phenol
hydrochloride
The product of Step C was empasted with 50 ml of water and an
excess of ammonium hydroxide was added thereto. The mixture was
extracted with ethyl acetate and the organic phase was washed with
water, dried and evaporated to dryness. The 11.55 g of orange oil
residue were added to 45 g of pyridine and the mixture was refluxed
at 220.degree. C. under an inert atmosphere for 135 minutes. The
mixture was cooled to 20.degree. C. and was made alkaline with
ammonium hydroxide. The mixture was then extracted with ethyl
acetate and the organic phase was washed with water, dried and
evaporated to dryness. The 12.8 g of reddish oil residue were
dissolved in 60 ml of isopropanol and an excess of ethyl acetate
saturated with hydrogen chloride was added thereto. The ethyl
acetate was distilled and crystallization was induced after which
the mixture was held overnight in a refrigerator. The mixture was
vacuum filtered and the recovered product was washed with
isopropanol and dried to obtain 9.3 g of
3-[2-({2-(1H-indol-3-yl)-ethyl}-propylamino)-ethyl]-phenol
hydrochloride in the form of a clear beige solid melting at
192.degree. C., then 197.degree. C. Crystallization of the product
from ethanol yielded a product melting at 198.degree. C.
Analysis: C.sub.21 H.sub.26 N.sub.2 O . HCl; molecular
weight=358.90 Calculated: %C 70.28; %H 7.58; %N 7.80; %Cl 9.88;
Found: %C 70.3; %H 7.7; %N 7.5; %Cl 10.1
UV Spectrum (ethanol):
Max.--220 nm E.sub.1.sup.1 =1149 .epsilon.=41,200
Max.--274 nm E.sub.1.sup.1 =214
Max.--280 nm E.sub.1.sup.1 =220 .epsilon.=7,900
Max.--289 nm E.sub.1.sup.1 =155 .epsilon.=5,550
Max.--362 nm E.sub.1.sup.1 =3
Max.--380 nm E.sub.1.sup.1 =4
Max.--403 nm E.sub.1.sup.1 =3.5
UV Spectrum (ethanol-0.1 NaOH):
Inflex.--240 nm E.sub.1.sup.1 =305 .epsilon.=10,950
Inflex.--275 nm E.sub.1.sup.1 =190
Max.--284 nm E.sub.1.sup.1 =232 .epsilon.=8,300
Max.--290 nm E.sub.1.sup.1 =233 .epsilon.=8,400
Inflex.--295 nm E.sub.1.sup.1 =166 .epsilon.=5,950
EXAMPLE 8
Tablets were prepared containing either 10 mg of
3-{[2-(cyclohexylethyl)-propylamino]-ethyl}-phenol hydrochloride or
3-[2-{propyl-(2-(2-thienyl)-ethyl]-amino}-ethyl]-phenol
hydrochloride and sufficient excipient of lactose, starch, talc and
magnesium stearate for a final weight of 200 mg.
PHARMACOLOGICAL DATA
A. Rotation after unilateral injury to nigrostriated fasciculus
with 6-hydroxydopamine
The test was conducted on groups of 6 male rats weighing about 250
g and the injury was caused by injection in the dark substance of 8
.mu.g of 6-hydroxydopamine hydrochloride dissolved in 4 .mu.l of
physiological serum containing 1 mg/ml of ascorbic acid [U
Ungerstedt, Acta physiol. Scand., Vol. 82 (1971), supp. 367, p.
69-93]. The test compounds were administered orally or
intraperitoneally and the animals were individually placed in a
rotometer which counted the number of rotations of each animal in 2
ways. Each test lasted for 90 minutes and under these conditions,
the compounds of Examples 2,3,5 and 7 showed contralateral
rotations at a dose of 0.5, 2.5 and 10 mg/kg, respectively when
administered intraperitoneally. These results show that the tested
compounds possess interesting dopaminergic stimulating
activity.
B. Acute toxicity
The 50% lethal dose (DL.sub.50) was determined for the products
after intraperitoneal administration to mice and the mortality was
determined 48 hours after the administration of the test product.
The DL.sub.50 for product of Example 1 was greater than 200 mg/kg
and for compound 2 was chart 150 mg/kg.
Various modifications of the products and methods of the invention
may be made without departing from the spirit or scope thereof and
it is to be understood that the invention is to be limited only as
defined in the appended claims.
* * * * *